Telethon Institute of Genetics and Medicine, Via Pietro Castellino 111, 80131 Naples, Italy.
Nature. 2013 Sep 5;501(7465):116-20. doi: 10.1038/nature12423. Epub 2013 Aug 4.
Newly synthesized proteins and lipids are transported across the Golgi complex via different mechanisms whose respective roles are not completely clear. We previously identified a non-vesicular intra-Golgi transport pathway for glucosylceramide (GlcCer)--the common precursor of the different series of glycosphingolipids-that is operated by the cytosolic GlcCer-transfer protein FAPP2 (also known as PLEKHA8) (ref. 1). However, the molecular determinants of the FAPP2-mediated transfer of GlcCer from the cis-Golgi to the trans-Golgi network, as well as the physiological relevance of maintaining two parallel transport pathways of GlcCer--vesicular and non-vesicular--through the Golgi, remain poorly defined. Here, using mouse and cell models, we clarify the molecular mechanisms underlying the intra-Golgi vectorial transfer of GlcCer by FAPP2 and show that GlcCer is channelled by vesicular and non-vesicular transport to two topologically distinct glycosylation tracks in the Golgi cisternae and the trans-Golgi network, respectively. Our results indicate that the transport modality across the Golgi complex is a key determinant for the glycosylation pattern of a cargo and establish a new paradigm for the branching of the glycosphingolipid synthetic pathway.
新合成的蛋白质和脂质通过不同的机制在高尔基复合体中运输，其各自的作用尚不完全清楚。我们之前鉴定了一种非囊泡的高尔基体内糖鞘脂（GlcCer）——不同糖脂系列的共同前体——的运输途径，该途径由细胞质 GlcCer 转移蛋白 FAPP2（也称为 PLEKHA8）（参考文献 1）操作。然而，FAPP2 介导的 GlcCer 从顺式高尔基体到反式高尔基体网络的转移的分子决定因素，以及通过高尔基体维持 GlcCer 的两种平行运输途径——囊泡和非囊泡——的生理相关性仍未完全定义。在这里，我们使用小鼠和细胞模型，阐明了 FAPP2 介导的 GlcCer 在高尔基体内向心性转运的分子机制，并表明 GlcCer 通过囊泡和非囊泡运输分别被引导到高尔基内质网和反式高尔基体网络中的两个拓扑上不同的糖基化轨迹。我们的结果表明，跨高尔基复合体的运输方式是货物糖基化模式的关键决定因素，并为糖脂合成途径的分支建立了一个新的范例。
